IUPHAR Review: Alpha6-containing GABAA receptors – Novel targets for the treatment of schizophrenia

Abstract

α6-containing GABA_A receptors (α6GABA_ARs) are strongly expressed in cerebellar granule cells and are of central importance for cerebellar functions. The cerebellum not only is involved in regulation of motor activity, but also in regulation of thought, cognition, emotion, language, and social behavior. Activation of α6GABA_ARs enhances the precision of sensory inputs, enables rapid and coordinated movement and adequate responses to the environment, and protects the brain from information overflow. The cerebellum has strong connections to multiple brain regions via closed loop circuits and is also extensively connected with the dopamine system in the prefrontal cortex, that initiates the execution of behavior. Patients suffering from schizophrenia exhibit an impaired structure and function of the cerebellum and an impaired GABAergic transmission at α6GABA_ARs. This also impairs the function of the dopamine system, can explain a variety of schizophrenia symptoms observed, and might be one of the pathophysiological causes of schizophrenia. Enhancing GABAergic transmission at α6GABA_ARs should thus reduce the symptoms of schizophrenia. This recently has been confirmed by demonstrating that positive allosteric modulators with high selectivity for α6GABA_ARs can reduce positive and negative symptoms and cognitive impairment of schizophrenia in several animal models of this disorder. So far, the beneficial actions of these modulators have been demonstrated in animal models of neuropsychiatric disorders, only. Future human studies have to investigate the safety and possible side effects of these modulators and to clarify, to which extent individual symptoms of schizophrenia can be reduced by these drugs in patients during acute and chronic dosing.